Project

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KRAB/KAP1 epigenetic regulation and pluripotent stem cell homeostasis

English title KRAB/KAP1 epigenetic regulation and pluripotent stem cell homeostasis
Applicant Trono Didier
Number 128157
Funding scheme NRP 63 Stem cells and regenerative medicine
Research institution Laboratoire de virologie et génétique FSV-GHI EPFL
Institution of higher education EPF Lausanne - EPFL
Main discipline Embryology, Developmental Biology
Start/End 01.03.2010 - 28.02.2015
Approved amount 981'970.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Molecular Biology

Keywords (7)

embryonic stem cells; gene silencing; KRAB zinc finger proteins; KAP1; endogenous retroelements; imprinting; DNA methylation

Lay Summary (English)

Lead
The embryonic stem cell is the mother of all cells constituting an organism, and its survival and proper development depend on the timely silencing of specific regions of its genome. This is larelgy accomplished by the so-called KRAB/KAP1 system, the focus of the present project.
Lay summary
The KRAB gene family and its role in the development of human beings

For embryonic stem cells to evolve into human beings, precise interplay and control within the 20,000 genes is essential. The KRAB-ZPF gene family plays an important role in this process but what exactly is its significance?

Background
Human beings and other higher mammals possess approximately 20,000 genes. These genes can be grouped in gene families which inherit different tasks. About 400 genes belong to the so-called KRAB-ZFP family. This gene family has a leading role because it can stop other genes from becoming active. They control other genes and guarantee that they are only activated at the right time in the development of mammals. They also play an important role in the development of embryonic stem cells.

But to date it remains unclear how exactly they do their work - how do they get into contact with other genes and which messengers they use? Didier Trono and colleagues from the EPF Lausanne will try to answer these questions within the next few years.

Aim
The aim is to improve our understanding of the role the important KRAB-ZPF-family plays in the development of all mammals.

Significance
This study should shed light on events which govern the earliest steps of embryonic development.

Direct link to Lay Summary Last update: 04.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation.
Singh Kulwant, Cassano Marco, Planet Evarist, Sebastian Soji, Jang Suk Min, Sohi Gurjeev, Faralli Hervé, Choi Jinmi, Youn Hong-Duk, Dilworth F Jeffrey, Trono Didier (2015), A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation., in Genes & development, 29(5), 513-25.
Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch.
Rauwel Benjamin, Jang Suk Min, Cassano Marco, Kapopoulou Adamandia, Barde Isabelle, Trono Didier (2015), Release of human cytomegalovirus from latency by a KAP1/TRIM28 phosphorylation switch., in eLife, 4, 0.
TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells.
Fasching Liana, Kapopoulou Adamandia, Sachdeva Rohit, Petri Rebecca, Jönsson Marie E, Männe Christian, Turelli Priscilla, Jern Patric, Cammas Florence, Trono Didier, Jakobsson Johan (2015), TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells., in Cell reports, 10(1), 20-8.
[A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy].
Barde Isabelle, Rauwel Benjamin, Marin-Florez Ray Marcel, Corsinotti Andrea, Laurenti Elisa, Verp Sonia, Offner Sandra, Marquis Julien, Kapopoulou Adamandia, Vanicek Jiri, Trono Didier (2014), [A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy]., in Médecine sciences : M/S, 30(1), 12-5.
As time goes by: KRABs evolve to KAP endogenous retroelements.
Imbeault Michael, Trono Didier (2014), As time goes by: KRABs evolve to KAP endogenous retroelements., in Developmental cell, 31(3), 257-8.
Evolutionally dynamic L1 regulation in embryonic stem cells.
Castro-Diaz Nathaly, Ecco Gabriela, Coluccio Andrea, Kapopoulou Adamandia, Yazdanpanah Benyamin, Friedli Marc, Duc Julien, Jang Suk Min, Turelli Priscilla, Trono Didier (2014), Evolutionally dynamic L1 regulation in embryonic stem cells., in Genes & development, 28(13), 1397-409.
Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network.
Gubelmann Carine, Schwalie Petra C, Raghav Sunil K, Röder Eva, Delessa Tenagne, Kiehlmann Elke, Waszak Sebastian M, Corsinotti Andrea, Udin Gilles, Holcombe Wiebke, Rudofsky Gottfried, Trono Didier, Wolfrum Christian, Deplancke Bart (2014), Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network., in eLife, 3, 03346-03346.
Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements.
Turelli Priscilla, Castro-Diaz Nathaly, Marzetta Flavia, Kapopoulou Adamandia, Raclot Charlène, Duc Julien, Tieng Vannary, Quenneville Simon, Trono Didier (2014), Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements., in Genome research, 24(8), 1260-70.
Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency.
Friedli Marc, Turelli Priscilla, Kapopoulou Adamandia, Rauwel Benjamin, Castro-Díaz Nathaly, Rowe Helen M, Ecco Gabriela, Unzu Carmen, Planet Evarist, Lombardo Angelo, Mangeat Bastien, Wildhaber Barbara E, Naldini Luigi, Trono Didier (2014), Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency., in Genome research, 24(8), 1251-9.
A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.
Barde Isabelle, Rauwel Benjamin, Marin-Florez Ray Marcel, Corsinotti Andrea, Laurenti Elisa, Verp Sonia, Offner Sandra, Marquis Julien, Kapopoulou Adamandia, Vanicek Jiri, Trono Didier (2013), A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy., in Science (New York, N.Y.), 340(6130), 350-3.
A switch between topological domains underlies HoxD genes collinearity in mouse limbs.
Andrey Guillaume, Montavon Thomas, Mascrez Bénédicte, Gonzalez Federico, Noordermeer Daan, Leleu Marion, Trono Didier, Spitz François, Duboule Denis (2013), A switch between topological domains underlies HoxD genes collinearity in mouse limbs., in Science (New York, N.Y.), 340(6137), 1234167-1234167.
De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.
Rowe Helen M, Friedli Marc, Offner Sandra, Verp Sonia, Mesnard Daniel, Marquis Julien, Aktas Tugce, Trono Didier (2013), De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET., in Development (Cambridge, England), 140(3), 519-29.
Global and stage specific patterns of Krüppel-associated-box zinc finger protein gene expression in murine early embryonic cells.
Corsinotti Andrea, Kapopoulou Adamandia, Gubelmann Carine, Imbeault Michael, Santoni de Sio Francesca R, Rowe Helen M, Mouscaz Yoann, Deplancke Bart, Trono Didier (2013), Global and stage specific patterns of Krüppel-associated-box zinc finger protein gene expression in murine early embryonic cells., in PloS one, 8(2), 56721-56721.
Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression.
Márquez C, Poirier G L, Cordero M I, Larsen M H, Groner A, Marquis J, Magistretti P J, Trono D, Sandi C (2013), Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression., in Translational psychiatry, 3, 216-216.
TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells.
Rowe Helen M, Kapopoulou Adamandia, Corsinotti Andrea, Fasching Liana, Macfarlan Todd S, Tarabay Yara, Viville Stéphane, Jakobsson Johan, Pfaff Samuel L, Trono Didier (2013), TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells., in Genome research, 23(3), 452-61.
The developmental control of transposable elements and the evolution of higher species
Friedli Marc, Trono Didier, The developmental control of transposable elements and the evolution of higher species, in Annual Revue Cell Develpment Biology.

Associated projects

Number Title Start Funding scheme
150831 A Chromatin Sharing Instrument for Analyses of Gene Regulation and Chromatin Structure 01.12.2013 R'EQUIP
152879 KRAB/KAP and the control of transposable elements 01.04.2014 Project funding
135713 Innate defenses against retroelements 01.04.2011 Project funding
133797 Biology Needs Ultra High Throughput DNA Sequencing 01.06.2011 R'EQUIP

Abstract

KAP1 is a transcriptional silencer that serves as universal cofactor to the hundreds of KRAB-zinc finger proteins encoded by the genomes of higher vertebrates. We previously demonstrated that the KRAB/KAP1 system is essential to the homeostasis of embfyonic stem cells as it is responsible for the silencing of endogenous retroelements, the maintenance of impriting marks, and the establishment of site-specific DNA methylation patterns conserved during development. In the second phase of this grant, we will further explore the molecular mechanisms of these events, and the roles played by particular KRAB-ZFPs in this process.
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